Clinical Research on HIV/AIDS Vaccines

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The National Institute of
Allergy and Infectious Diseases (NIAID) conducts
clinical trials of candidate vaccines to discover
which might most successfully protect people from
human immunodeficiency virus (HIV) infection (preventive
vaccine) or from becoming ill after they
acquire the virus (therapeutic vaccine).
(Throughout this fact sheet scientific terms
common to vaccine research have been printed in
bold-faced
type and defined.)

Scientists have identified
important immunologic targets on HIV and on
infected cells. For example, they know that the
glycoprotein 120 (gp120) on the outer coat of the
virus contains the region that attaches to cells
of the host, the CD4 binding site.
Scientists also know that most neutralizing
antibodies (proteins that block a virus from
infecting cells) in HIV-infected people are
directed against gp120. For these reasons,
vaccines based on genetically engineered HIV envelope
proteins -- gp160 and one of its cleavage
products, gp120 -- have been the most well-studied
to date.

More than 40 experimental
HIV vaccines have been tested in humans
worldwide. Vaccine approaches in development or
in clinical trials include the following:

subunit vaccine:
a piece of the outer surface of HIV, such
as gp160 or gp120, produced by genetic
engineering.

recombinant
vector vaccine: a live bacterium
or virus such as vaccinia (used in the
smallpox vaccine) modified to transport
into the body a gene that makes one or
more HIV proteins.

vaccine
combination: for example, use of
a recombinant vector vaccine to induce
cellular immune responses followed by
booster shots of a subunit vaccine to
stimulate antibody production, referred
to as a prime-boost strategy.

whole-inactivated
virus vaccine: HIV that has been
inactivated by chemicals, irradiation or
other means so it is not infectious.

live-attenuated
virus vaccine: live HIV from
which one or more apparent
disease-promoting genes of the virus have
been deleted.

Clinical Trials Background

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After an experimental
vaccine performs well in preclinical safety
and immunogenicity tests, it must
successfully complete three stages of testing
in people before development into a licensed
product.

A Phase I trial
is the first setting in which an experimental
HIV vaccine is given to people. Such a trial
enrolls about 20 to 80 non-HIV-infected
volunteers at apparent low risk of HIV
infection. A Phase I trial primarily seeks
information on safety, usually assessing any
vaccine-related side effects by comparing the
vaccine with an inactive placebo or control
that looks like the test product. A Phase I
trial also can provide data on the vaccine's
immunogenicity, including the dose and
administration schedule required to achieve
optimal immune responses. If the vaccine
elicits neutralizing antibodies, scientists
can study how these react against HIV strains
from the same or other clades to determine
the potential breadth of protection. A Phase
I trial may last one to two years.

Once Phase I trials
show that the experimental HIV vaccine is
well-tolerated, it can advance into Phase
II trials. These trials enroll more
people, up to a few hundred, and often
include some volunteers at higher risk for
acquiring HIV. Researchers gather data about
safety and immune responses, asking more
sophisticated questions that such larger
trials allow. Optimally, the trials are randomized
and double-blind, meaning that
volunteers are assigned at random to a study
group and that neither the health care
workers nor the patients know what
preparations the patients receive. Phase II
trials usually last one to two years.

The most promising
candidate vaccines move into Phase III
or efficacy trials, enrolling large
numbers of non-HIV-infected people at high
risk for exposure to the virus. A Phase III
trial usually is designed to ensure the
collection of enough data on safety and
effectiveness to support a license
application, if warranted. The vaccine may be
tested against a placebo or a vaccine such as
hepatitis B of known potential benefit to the
study population. An efficacy trial can
involve thousands of volunteers and therefore
takes much longer, at least four years, to
complete.

Clinical Trials of Preventive Vaccines

In August 1987, NIAID
opened the first clinical trial of an
experimental HIV vaccine at the NIH Clinical
Center in Bethesda, Md. This safety trial
eventually enrolled 138 non-infected healthy
volunteers. The gp160 subunit candidate
vaccine tested caused no serious adverse
effects.

Since the first trial,
more than 40 preventive HIV vaccine trials
have been initiated worldwide. These Phase
I/II trials examine the vaccine's safety and
provide preliminary information on its
ability to stimulate immune responses.

The NIAID AIDS
Vaccine Evaluation Group (AVEG) is
the largest U.S. cooperative HIV vaccine
clinical trials group. The AVEG, which began
enrolling volunteers in February 1988,
includes the following:

The AIDS Vaccine Evaluation Units (AVEUs),
located at six U.S. research centers,
conduct Phase I and II clinical
trials of candidate HIV vaccines in
low-risk and high-risk
HIV-seronegative volunteers.

The Central
Immunology Laboratory
provides state-of-the-art evaluation
of humoral and cellular immune
responses of vaccinees in AVEG
trials. The evaluations use
standardized tests, permitting
comparison of responses in different
individuals and to different
candidate vaccines.

The Data
Coordinating and Analysis Center
provides a central facility for
collecting and analyzing data from
the trials conducted by the AVEUs.

The Immunology
Laboratory Support for Assessment of
Mucosal Immune Responses Induced by
AIDS Vaccines evaluates human
mucosal immune responses to candidate
vaccines in standardized tests,
permitting the comparison of
responses in volunteers at different
AVEUs and in volunteers who receive
different candidate vaccines.

The Specimen
Repository collects and
maintains blood samples and other
specimens from volunteers in AVEG
trials for use in current and future
studies.

As of January 1997,
more than 2,000 men and women have
participated in preventive HIV vaccine trials
conducted at six medical center AVEU sites
located in Baltimore, Nashville, Seattle, St.
Louis, Birmingham and Rochester, N.Y.

To date, all the
vaccine candidates tested have been
well-tolerated, generally producing only mild
side effects typical of most vaccines. The
first candidates tested stimulated production
of antibodies, although levels decreased
within a relatively short period of time.
Initial formulations and dosages of these
vaccines produced few or low levels of
neutralizing antibodies and rarely elicited cytotoxic
T cells, which are invoked through
cell-mediated immunity to kill HIV-infected
cells.

With newer protocols,
using increased vaccine dosages, different
immunization schedules, experimental
adjuvants and new recombinant proteins, more
promising data regarding the induction of
neutralizing antibodies and cytotoxic T cells
have emerged.

In December 1992, NIAID
launched the first Phase II HIV vaccine
clinical trial. Earlier trials enrolled
non-infected people at low risk of HIV
infection and primarily sought data on
safety. This trial includes non-infected
volunteers with a history of high-risk
behavior--injection drug use, multiple sex
partners or sexually transmitted diseases.
Participants are counseled repeatedly to
avoid any behavior that puts them at risk of
HIV infection. Follow-up for this trial has
been extended to four years.

The trial will help
determine if these distinct populations,
representative of people likely to be
enrolled in large-scale efficacy trials,
respond differently to vaccines. The trial
also will provide more detailed data on the
safety and ability of vaccines to stimulate
immune responses.

A second Phase II HIV
vaccine clinical trial is now under way at
AVEU sites and in the HIV Network for
Prevention Trials (HIVNET).

Experimental HIV
vaccines are growing in number and kind.
Clinical trials will yield valuable
information about the relative effects on
immune response of different formulations and
delivery methods.

Future Directions

Although the challenges
are daunting, scientists remain optimistic
that safe and effective HIV vaccines can be
developed. Novel ways to present HIV proteins
to the immune system continue to be designed
and tested, as do new antigen/adjuvant
vaccine formulations. A growing number and
variety of experimental vaccines are entering
clinical tests in primates and humans, and
more trials are exploring whether changing
immunization schedules, increasing booster
doses or using a combination vaccine strategy
can stimulate stronger, more durable immune
responses. Together, progress in basic and
clinical research is moving scientists closer
toward identifying products suitable for
large-scale HIV vaccine efficacy trials.

A note from TheBody.com: The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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